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Biomedical subjects

P A Wilson

Publications and source records attributed to P A Wilson.

At least 19 recordsLinked to original sources
PubMed2005

Severe community-acquired pneumonia: an Australian perspective.

BACKGROUND: Severe community-acquired pneumonia (CAP) is a common disease with a relatively high mortality. The initial treatment is empirical, based on a broad range of potential pathogens. There are minimal published data describing microbiological causes of pneumonia in Australia. AIMS: To describe the aetiology and characteristics of severe CAP in patients requiring intensive care unit (ICU) admission, to identify factors predicting mortality and to audit current practices of investigation and antibiotic management of these patients from an Australian perspective. METHODS: A retrospective analysis of patient case notes was performed for 96 consecutive patients admitted to two ICU with severe CAP. Data recorded included patient demographics, comorbidities, antimicrobial treatment, investigations and outcome (mortality, length of stay). RESULTS: Overall, mortality was 32%. A microbiological diagnosis was made in 46% of patients. The most frequent causative organisms were Streptococcus pneumoniae (13 cases), influenza A (9), Haemophilus influenzae (5) and Staphylococcus aureus (4); aerobic Gram-negative bacilli collectively accounted for five cases. Blood cultures were positive in 20% of patients. Seventy patients (73%) required mechanical ventilation and 61 patients (63%) required inotropic support. Laboratory abnormalities including acute renal failure, metabolic acidosis and coagulopathy were frequent. Factors associated with mortality on multivariate analysis were age, antibiotic administration prior to hospital presentation, delay in hospital antibiotic administration of more than 4 h, and presence of multilobar or bilateral consolidation on chest X-ray. CONCLUSIONS: Severe CAP requiring ICU admission was associated with a mortality rate of 32%, despite appropriate antimicrobial therapy including a beta-lactam and a macrolide antibiotic in most cases. Causative organisms identified were similar to those found in previous studies. High rates of viral causes (28% of identified pathogens) were noted. Low rates of legionellosis and other atypical causes were found, most probably due to a lack of systematic testing for these agents.

Adult↗
PubMed2001

Warm tropical ocean surface and global anoxia during the mid-Cretaceous period.

The middle of the Cretaceous period (about 120 to 80 Myr ago) was a time of unusually warm polar temperatures, repeated reef-drowning in the tropics and a series of oceanic anoxic events (OAEs) that promoted both the widespread deposition of organic-carbon-rich marine sediments and high biological turnover. The cause of the warm temperatures is unproven but widely attributed to high levels of atmospheric greenhouse gases such as carbon dioxide. In contrast, there is no consensus on the climatic causes and effects of the OAEs, with both high biological productivity and ocean 'stagnation' being invoked as the cause of ocean anoxia. Here we show, using stable isotope records from multiple species of well-preserved foraminifera, that the thermal structure of surface waters in the western tropical Atlantic Ocean underwent pronounced variability about 100 Myr ago, with maximum sea surface temperatures 3-5 degrees C warmer than today. This variability culminated in a collapse of upper-ocean stratification during OAE-1d (the 'Breistroffer' event), a globally significant period of organic-carbon burial that we show to have fundamental, stratigraphically valuable, geochemical similarities to the main OAEs of the Mesozoic era. Our records are consistent with greenhouse forcing being responsible for the warm temperatures, but are inconsistent both with explanations for OAEs based on ocean stagnation, and with the traditional view (reviewed in ref. 12) that past warm periods were more stable than today's climate.

Animals↗
PubMed2001

Axis induction by wnt signaling: Target promoter responsiveness regulates competence.

The modulation of inductive competence is a major theme in embryonic development, but, in most cases, the underlying mechanisms are not well understood. In principle, the capacity of extracellular signals to elicit particular responses could be regulated by changes in cell surface receptors, in intracellular signaling pathways, or in the responsiveness of individual target gene promoters. As an example of regulated competence, we have examined dorsal axis induction in Xenopus embryos by Wnt signaling. Competence of Wnt proteins such as Xwnt-8 to induce an ectopic axis or the dorsal early response genes siamois and Xnr3 is lost by the onset of gastrulation, when these same ligands now produce a distinct set of "late" effects, including anterior truncation and induction of the midbrain/hindbrain marker engrailed-2. Although other Wnts apparently make use of alternative signaling mechanisms, we demonstrate that late-expressed Xwnt-8 continues to employ the canonical Wnt signaling pathway used earlier in dorsal axis induction, stabilizing cytosolic beta-catenin, and activating gene expression through Tcf/Lef transcription factors. Moreover, an activated, hormone-inducible version of XTcf-3 (TVGR) that can reproduce both early and late Wnt responses when activated at appropriate stages becomes unable to induce siamois and secondary axes at the same time as Wnt ligands themselves. Finally, we show that TVGR also loses the ability to induce expression of a reporter construct containing a small fragment of the siamois promoter, implying that this fragment contains sequences governing the loss of Wnt responsiveness before gastrulation. Together, these results argue that the competence of Wnts to induce a dorsal axis is lost in the nucleus, as a result of changes in the responsiveness of target promoters.

Animals↗
PubMed2000

Serotonin transporter inhibitors: synthesis and binding potency of 2'-methyl- and 3'-methyl-6-nitroquipazine.

Racemic 2'-methyl- and 3'-methyl-6-nitroquipazine ligands were selected as targets, synthesized and evaluated at the serotonin transporter employing an in vitro competitive inhibition assay with [3H]paroxetine and rat cortical membrane. The 2'-methyl-6-nitroquipazine was found to be 50 times more potent than the 3'-methyl-substituted counterpart and of comparable potency to the known high affinity agent 5-iodo-6-nitroquipazine.

Animals↗
PubMed1997

Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1.

Morphogens are thought to establish pattern in early embryos by specifying several cell fates along a gradient of concentration; a well-studied example is the Drosophila protein decapentaplegic (DPP) acting in the wing disc. Recent work has established that bone morphogenetic protein 4 (BMP4), the vertebrate homologue of DPP, controls the fundamental choice between neural and epidermal fates in the vertebrate ectoderm, under the control of antagonists secreted by the organizer region of the mesoderm. We now show that BMP4 can act as a morphogen, evoking distinct responses in Xenopus ectodermal cells at high and low concentrations, in a pattern consistent with the positions of the corresponding cell types in the embryo. Moreover, this complex cellular response to extracellular BMP4 concentration does not require subsequent cell-cell communication and is thus direct, as required of a classical morphogen. We also show that the same series of cell types--epidermis, cement gland and neural tissue--can be produced by progressively inhibiting endogenous BMP signaling with specific antagonists, including the organizer factor noggin. Finally, expression of increasing doses of the signal transduction molecule Smad1 accurately reproduces the response to BMP4 protein. Since Smads have been shown to act in the nucleus, this finding implies a direct translation of extracellular morphogen concentration into transcription factor activity. We propose that a graded distribution of BMP activity controls the specification of several cell types in the gastrula ectoderm and that this extracellular gradient acts by establishing an intracellular and then nuclear gradient of Smad activity.

Animals↗
PubMed1997

A Xenopus type I activin receptor mediates mesodermal but not neural specification during embryogenesis.

Activins and other ligands in the TGFbeta superfamily signal through a heteromeric complex of receptors. Disruption of signaling by a truncated type II activin receptor, XActRIIB (previously called XAR1), blocks mesoderm induction and promotes neuralization in Xenopus embryos. We report the cloning and characterization of a type I activin receptor, XALK4. Like truncated XActRIIB, a truncated mutant (tXALK4) blocks mesoderm formation both in vitro and in vivo; moreover, an active form of the receptor induces mesoderm in a ligand-independent manner. Unlike truncated XActRIIB, however, tXALK4 does not induce neural tissue. This difference is explained by the finding that tXALK4 does not block BMP4-mediated epidermal specification, while truncated XActRIIB inhibits all BMP4 responses in embryonic explants. Thus, the type I and type II activin receptors are involved in overlapping but distinct sets of embryonic signaling events.

Activin Receptors↗
PubMed1996

Development of a simplified polymerase chain reaction-enzyme immunoassay for the detection of Chlamydia pneumoniae.

The 16S rRNA genes of two Chlamydia pneumoniae and two C. psittaci strains of different serovars were sequenced then compared to previously reported Chlamydia 16S rRNA gene sequences. Chlamydia pneumoniae-specific regions were identified and specific primers for nested PCR were synthesized. Nested PCR reactions were performed, in a single tube, by varying the annealing temperature of the amplification cycles. The initial thermal cycles were selected to allow annealing and extension of only the outer primer pair, whilst in later cycles a temperature that allowed inner primer annealing was employed. The inner primers were labelled, one with biotin and the other with fluorescein and consequently the dual labelled amplicon could be immobilized onto antibiotin-coated microtitre plates and detected colorimetrically via an antifluorescein-enzyme conjugate. The assay was found to be sensitive and specific. No cross reactions were observed with C. trachomatis, C. psittaci or other common respiratory pathogens.

Chlamydophila pneumoniae↗
PubMed1996

High frequency of aberrant p16(INK4A) expression in human breast cancer.

The product of the CDKN2/MTS1 gene, p16(INK4A) (16), inhibits phosphorylation of the retinoblastoma protein, pRB, and thus acts as a negative cell cycle regulator. It is inactivated in a wide range of human malignancies, including breast cancer. Using an immunohistochemical approach, we studied the expression of both p16 and pRB in 104 archival breast tumors, including 63 ductal, 33 lobular, and 8 mixed carcinomas. All specimens except one were evaluable for pRB expression, but only 87 were interpretable for p16 expression, reflecting the lower abundance and greater lability of this protein. Only six tumors showed abnormal RB expression. However, 43 carcinomas (49%) were completely (35) or focally (8) negative for p16. Abnormal p16 expression did not significantly correlate with several histopathological parameters. These findings provide evidence that aberrant p16(INK4A) expression is one of the most common abnormalities in human breast cancer.

Breast Neoplasms↗
PubMed1995

Induction of epidermis and inhibition of neural fate by Bmp-4.

During gastrulation in vertebrates, ectodermal cells choose between two fates, neural and epidermal. The nervous system forms in response to signals from the Spemann organizer; ectoderm that does not receive these signals becomes epidermis. Unexpectedly, however, in Xenopus, neural tissue also forms when cell-cell communication within the ectoderm is disrupted by cell dissociation or by antagonists of the growth factor activin. These observations suggest that epidermal specification depends on local signalling, by activin or a close relative, and that neural tissue forms when this communication is blocked. Here we report that bone morphogenesis protein 4 (Bmp-4), a relative of activin that is expressed in the embryo at the time of ectodermal fate determination, is a potent epidermal inducer and neural inhibitor, the first reported in any vertebrate. Activin can inhibit neuralization by inducing mesoderm, but does not induce epidermis. Moreover, the dominant-negative activin receptor, which stimulates neuralization when expressed in the embryo, blocks Bmp-4 in our assay. Our findings demonstrate that epidermal fate can be induced, and thus provide further evidence that neural specification is under inhibitory control in vertebrates.

Activin Receptors↗
PubMed1994

Mesodermal patterning by an inducer gradient depends on secondary cell-cell communication.

BACKGROUND: Gradients of inducing molecules, or morphogens, could impose pattern on early embryos. Although there are candidates for morphogens in several systems, it is not well understood how cells might translate differences in extracellular inducer concentration into an orderly arrangement of cell types. With this question in mind, we have re-examined mesodermal patterning in Xenopus in response to the secreted growth factor activin. Previous work has shown that activin can initiate the formation of a variety of mesodermal tissues in a concentration-dependent fashion. We have sought to disentangle the roles played by individual cell responses to activin and subsequent interactions among induced cells in producing this outcome. RESULTS: We find that the initial response of dispersed cells to activin concentration is unexpectedly simple, showing neither the thresholds of activin concentration nor the distinct domains of gene expression that characterize the later response. The eventual emergence of an ordered series of coherent differentiation steps requires the reaggregation of the induced cells, implying that secondary interactions occur. Furthermore, when cells induced at different doses of activin are mixed, the final response apparently represents a consensus, rather than a mosaic, of the mixed populations. CONCLUSIONS: We conclude that communication among responding cells underlies much of the remarkable patterning influence of activin. Moreover, we suggest that these findings can inform thinking about how inducer gradients might act in other systems, shifting emphasis from the initial response of cells to inducer concentration toward the elaboration of complex pattern by secondary interactions.

Actins↗